tbuckley/cabot-search huggingface dataset:
Abstract 621: ZL-1211 exhibits robust anti-tumor activity by enhancing ADCC and activating innate and adaptive immunity in CLDN18.2-high and -low expressing gastric cancer models
Authors: Hiroyasu Konno, Tracey Lin, Bee-Chun Sun, Renyi Wu, Christopher Szeto, David Bellovin, Karl Hsu, Omar Kabbarah
Journal: Cancer Research (2022)

Abstract CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in ~30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in the majority of low expressing malignancies. ZL-1211 is a monoclonal antibody targeting CLDN18.2 engineered to promote enhanced ADCC with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors than the leading clinical benchmark. To further assess the potency of ZL-1211, we utilized a panel of gastric tumor cell lines that endogenously express CLDN18.2 and more accurately reflect target levels in human gastric tumors than engineered overexpressing models. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also -low expressing gastric cell lines. Greater anti-tumor efficacy was also observed in mouse xenograft models with CLDN18.2-high, -medium, and low-expressing gastric cell lines in response to treatment with ZL-1211 compared to the clinical benchmark. NK cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment, as CLDN18.2-expressing gastric tumors grown in Balb/c nude with an intact NK function were sensitive to ZL-1211 treatment, while NOD-SCID with partially competent NK activity exhibited minimal response, and NCG without NK cells did not display any evidence of in vivo efficacy. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL-6 production. Interestingly, ZL-1211 treatment led to NK cell and monocyte stimulation and enhanced CD8+ T cell activation, suggesting a mechanism of action that not only involves innate but also adaptive immunity. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that are not eligible for treatment with the leading clinical benchmark by inducing a robust ADCC response and activating innate and adaptive immunity to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710). Citation Format: Hiroyasu Konno, Tracey Lin, Bee-Chun Sun, Renyi Wu, Christopher Szeto, David Bellovin, Karl Hsu, Omar Kabbarah. ZL-1211 exhibits robust anti-tumor activity by enhancing ADCC and activating innate and adaptive immunity in CLDN18.2-high and -low expressing gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 621.
Plaque Burden and 1-Year Outcomes in Acute Chest Pain
Authors: Mohammed N. Meah, Evangelos Tzolos, Kang-Ling Wang, Anda Bularga, Marc R. Dweck, Nick Curzen, Attila Kardos, Liza Keating, Robert F. Storey, Nicholas L. Mills, Piotr J. Slomka, Damini Dey, David E. Newby, Alasdair Gray, Michelle C. Williams, Carl Roobottom
Journal: JACC. Cardiovascular imaging (2022)
Abstract 5695: Roles of cGAS in DNA damage response
Authors: Weidong Chen, Hyun-Jung An, Ga-Eun Lee, Yong-Yeon Cho
Journal: Cancer Research (2022)

Abstract Cytosolic double strand DNAs released from the nucleus or mitochondria produce diverse cellular signals mediated by cyclic GAM-AMP synthase (cGAS) to modulate cell proliferation, metastasis, apoptosis, and necroptosis. However, the role of cGAS has not been fully elucidated when cells are stimulated with DNA damage response such as ultraviolet (UV). In this study, we found that DNA damage by treatment of cisplatin or UVB induced cGAS protein levels. We further found that cisplatin and UVB increased not only endogenous cGAS protein levels, but also ectopic expressed cGAS protein levels. The cGAS protein increase was showed positive correlation with H2AX phosphorylation at Ser139 (γH2AX). Moreover, although UVB stimulation suppressed cell proliferation in both stably expressing mock control (SK-MEL-2-mock) and cGAS in SK-MEL-2 (SK-MEL-2-cGAS) cells, suppression ratio in SK-MEL-2-cGAS cells was reduced compared to SK-MEL-2-mock cells. These results suggested that cGAS may have a potential to cell protection when the cells are stimulated with DNA damage. This hypothesis was supported by that cell proliferation of SK-MEL-2-cGAS cells were 2 folds faster than that of SK-MEL-2-mock cells after UVB stimulation. We further found that living cell population of SK-MEL-2-cGAS cells, which were 80% in no UVB stimulation, was reduced to 37% at 24 h and 34% at 48 h after 2 mJ/cm2 UVB stimulation, while SK-MEL-2-mock cells were reduced to 37% at 24 h and 20% at 48 h after 2 mJ/cm2 UVB stimulation. On the other hand, total cell death about 40% at 24 h and 65% at 48 h in SK-MEL-2-mock cells was reduced about 25% at 24 h and 36% at 48 h in SK-MEL-2-cGAS cells after 2 mJ/cm2 UVB stimulation. Taken together, we concluded that cGAS may play an important role to protect the cells from DNA damage. Citation Format: Weidong Chen, Hyun-Jung An, Ga-Eun Lee, Yong-Yeon Cho. Roles of cGAS in DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5695.
Abstract 1359: Selective HDAC6 inhibition by GB-1101 revokes tumor immune privilege and synergizes with immune checkpoint therapies to induce tumor regressions
Authors: Kari Kotlarczyk, Mario Sepulveda, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately
Journal: Cancer Research (2022)

Abstract HDAC6 is a cytoplasmic class IIB HDAC isoenzyme that is involved in the deacetylation of cytoplasmic proteins. HDAC6 also binds ubiquitinated proteins, facilitating the formation of the aggresome, to remove misfolded proteins. Previously, HDAC6-selective inhibitors were shown to decrease immunosuppression and enhance immune function of melanoma patient T-cells demonstrating an important role for HDAC6 inhibition for cancer immunotherapy. GB-1101 is a novel, orally bioavailable, nanomolar potent inhibitor of HDAC6. GB-1101 tested in vitro did not induce direct cytotoxicity to CD4+/CD8+ or NK cells at concentrations up to 300 nM. RNA-seq on GB-1101 exposed MHC-null human MSS colon cancer cell lines reveal potent induction of MHC Class I/II genes and expression numerous cancer neoantigens. To test the activity of GB-1101 in vivo, we established large (~450mm3) 4T1-luc syngeneic tumors and initiated treatment of GB-1101 given orally once daily alone and combined with anti-PD1, anti-CTLA4, and anti-PD1/anti-CTLA4 combination. The activity of anti-PD1 in this model was minimal (TGI: 3%); GB-1101 as a single agent showed more potent anti-tumor activity (TGI: 50%) compared to anti-PD1. We observed synergistic benefit when GB-1101 was combined with anti-PD1 (Combination TGI: 78%). GB-1101 showed comparable anti-tumor activity to single agent anti-CTLA4 (TGI: 43%) but revealed significant tumor regressions of large and well-established tumors when combined with anti-CTLA4 (Combination TGI: &amp;gt;100%). As a single agent, GB-1101 was superior to anti-PD1+anti-CTLA4 (TGI: 7%) and induced significant tumor regressions when combined with anti-PD1+anti-CTLA4 (Triple Combination TGI: &amp;gt;100%). In the TC-1, HPV-positive syngeneic model, GB-1101 reprogrammed the tumor immune microenvironment reducing the number of M-MDSC and TReg cells and increase the numbers of CD4+/CD8+ and NK cells. Taken together, these data support GB-1101 as an important new targeted epigenetic immunomodulator able to revoke immune privilege to enhance the clinical activity of immune checkpoint therapies. Citation Format: Kari Kotlarczyk, Mario Sepulveda, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately. Selective HDAC6 inhibition by GB-1101 revokes tumor immune privilege and synergizes with immune checkpoint therapies to induce tumor regressions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1359.
Abstract 5503: Tumor-resilient T-cell signatures identify cellular therapy response biomarkers and reveal FIBP inhibition as an immunotherapy potentiator
Authors: Peng Jiang, Yu Zhang
Journal: Cancer Research (2022)

Abstract Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (Tumor-resilient T cell), a computational model and web server that utilizes single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as TGFβ, TRAIL, and PGE2. Analyzing transcriptomic data from pretreatment or pre-manufacture patient samples, Tres reliably predicts the clinical effectiveness of immune checkpoint blockade or adoptive cell transfer in melanoma, lung, and B-cell malignancies. Further, Tres identified FIBP as the top negative marker of tumor-resilient T cells across many cancers. FIBP knockouts in murine and human CD8 T cells significantly enhanced T-cell mediated cancer-killing and adoptive cell therapy by limiting cholesterol metabolism, which otherwise inhibits effector T-cell function. These results demonstrate Tres’s utility in identifying clinical biomarkers of T-cell effectiveness and potential therapeutic targets for enhancing immunotherapies in solid tumors. Citation Format: Peng Jiang, Yu Zhang. Tumor-resilient T-cell signatures identify cellular therapy response biomarkers and reveal FIBP inhibition as an immunotherapy potentiator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5503.
Abstract 1354: Regulation and roles of polyamines in CD8+ T cell fate and function
Authors: Aya G. Elmarsafawi, Rebecca S. Hesterberg, John L. Cleveland
Journal: Cancer Research (2022)

Abstract CD8+ T cells play central roles in tumor immune surveillance and are major effectors in adoptive cell therapy (ACT). Thus, strategies that enhance their functions are an urgent clinical need. Metabolic reprogramming determines T cell fate and function, where glycolysis principally drives an effector phenotype while oxidative phosphorylation (OxPhos) drives T cell memory [1]. However, the roles of amino acid catabolism in controlling effector and memory CD8+ T cell fate and function are less well understood [1, 2]. Glutamine is essential for nucleotide biosynthesis and as an anaplerotic fuel source for the tricarboxylic acid (TCA) cycle. Isotope tracing experiments with 13C glutamine or 13C arginine revealed that glutamine is the major source of polyamines in activated CD8+ T cells. Further, activation of CD8+ T cells provokes marked increases in the expression and activity of enzymes that direct polyamine biosynthesis, specifically ornithine decarboxylase (Odc), spermidine synthase (Srm) and spermine synthase (Sms), as well as to increases in the polyamines putrescine, spermidine and spermine. Notably, pharmacologic inhibition of Odc using difluoromethylornithine (DFMO), or genetic deletion of Odc using CD8+ T cells from CD4-Cre;Odcfl/fl mice, augments cytokine production in activated CD8+ T cells, including IFN-γ, TNF-α and granzyme B. Further, metabolic flux analysis indicates that DFMO treatment switches the metabolism of activated CD8+ T cells to rely on OxPhos, a phenotype found in CD8+ tissue resident memory (TRM) cells that play key roles in tissue and anti-tumor immunity anti-tumor reactivity. Indeed, inhibition or loss of Odc augments other TRM phenotypes, including increases in CD69high;CD44high;S1PR1low;CD62Llow cells that define the TRM phenotype. In addition, ACT of DFMO treated CD8+ T cells augments their survival in vivo and augments the generation of CD69+CD103+CD69+CXCR6+ and Ly6C+ TRMs in the bone marrow. Finally, DFMO treatment enhances IFN-γ and TNF-α production in human TILs, and co-treatment with TGF-β polarizes TILs into CD69+CD103+ and CD69+CD49a+ TRM-like cells. We conclude that polyamines are a metabolic check point in CD8+ TRM generation and are an actionable target to improve the anti-tumor immunity of T-cell based immunotherapies. Citation Format: Aya G. Elmarsafawi, Rebecca S. Hesterberg, John L. Cleveland. Regulation and roles of polyamines in CD8+ T cell fate and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1354.
Abstract 2544: Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs
Authors: Xiang Cheng, Hongji Zhang, Allan Tsung, Hai Huang
Journal: Cancer Research (2022)

Abstract Introduction: Under surgical trauma, the pathological amplification and activation of neutrophils with potent immunosuppressive functions, also known as polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs), can promote metastasis by forming neutrophil extracellular traps (NETs) that are web-like structures consisting of nuclear DNA, histones, and granule proteins. Preoperative exercise (PEx) reduces postoperative complications with improved clinical outcomes in cancer patients undergoing surgeries. are. Our preliminary data show that PEx suppresses liver ischemia/reperfusion (I/R)-induced colorectal cancer (CRC) liver metastasis. Our recent studies have shown I/R-induced NETs promote liver CRC metastasis by capturing tumor cells and preventing infiltration and cytotoxicity of CD8+ T cells in tumor microenvironment (TME). We hypothesize that PEx remodels the TME by suppressing PMN-MDSCs formation of NETs. Methods: Male mice were subjected to exercise for 4 weeks, before MC38 colorectal cancer cells were injected through portal vein, and then subjected to 70% partial liver warm I/R as surgical stress. The single-cell RNA sequencing (scRNA-seq) was performed on CD45+leukocytes from TME 3 weeks after surgery. Immunofluorescence staining and Western Blot were used to determine NETs formation in the TME. Flow cytometry was used to determine the infiltration of PMN-MDSCs and CD8+ T lymphocytes in the tumors. Results: Our scRNA-seq data reveal that PEx leads to a remarkable transcriptomic shift in most immune cells types, such as PMN-MDSCs, M-MDSCs, T cells, Kupffer cells, B cells, NK and NKT cells, in the TME. PEx decreases the percentages of PMN-MDSCs in the TME and inhibits theNETs formation by PMN-MDSCs. scRNA-seq shows a significant increase of the chemokines CXCL10 in PEx-trained PMN-MDSCs obtained 3 weeks after I/R-induced hepatic metastasis, compared with sedentary controls. In addition, PEx increases the number of CD8+ T lymphocytes infiltrating the TME. Summary: Our study shows that PEx downregulates NETs formation and increases the CXCL10 expression in PMN-MDSCs, thus promoting the recruitment more cytotoxic CD8 T lymphocytes to suppress tumor metastasis. Citation Format: Xiang Cheng, Hongji Zhang, Allan Tsung, Hai Huang. Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2544.
Abstract 1618: OP-1250 prevents tumor spread in a model of metastatic mutant ERα+ breast cancer
Authors: Muriel Laine, Marianne E. Greene, Tiffany Leng, Sophia Li, Gopinath S. Palanisamy, Cyrus L. Harmon, Leslie Hodges-Gallagher, Peter J. Kushner, Geoffrey L. Greene
Journal: Cancer Research (2022)

Abstract Estrogen receptor positive (ER+) breast cancers represent about 70-75% of all breast cancer. In general, these cancers are effectively treated with adjuvant endocrine therapies, with or without the addition of CDK4/6 inhibitors. However, many patients develop resistance and eventually progress to metastatic disease (MBC). Acquired mutations in ESR1, which encodes estrogen receptor alpha (ERα), contribute to 20-40% of endocrine therapy resistant MBC. In patients, breast cancer metastasis occurs in the liver, lungs, brain and bone. OP-1250 is a novel compound that is a complete ERα antagonist (CERAN). Previous studies have shown that OP-1250 effectively blocks both the AF-1 and AF-2 activation functions of ERα. In the current study, we used a mutant ERα MBC endocrine therapy resistant xenograft model to examine the efficacy of OP-1250 in a metastatic context. MCF7 cells engineered to express one of the most common and aggressive ERα mutations, Y537S, were labeled with luciferase and injected via the nipple (mammary intraductal MIND model) into NSG mice. Mice were treated with 3 and 10 mg/kg of OP-1250 alone or in combination with palbociclib at 70mg/kg and tumor growth was monitored via a Xenogen IVIS imager. At study end point, mice were sacrificed and excised organs were imaged ex-vivo and further processed for immunohistology analysis. OP-1250 at both doses inhibited primary tumor growth as well as metastasis to the lung, liver, brain and bone, with greater effect at 10 mg/kg, and was significantly more effective than Faslodex. When combined with palbociclib at 70 mg/kg, an additional significant decrease in metastasis was observed, compared to OP-1250 or palbociclib alone. Our results also suggest that the efficacy seen in the combination study was driven primarily by OP-1250. In total, these results demonstrate the potential use of OP-1250, both alone and in combination with a CDK4/6 inhibitor, to inhibit tumor growth and metastasis in a model of aggressive mutant ER+ MBC. Citation Format: Muriel Laine, Marianne E. Greene, Tiffany Leng, Sophia Li, Gopinath S. Palanisamy, Cyrus L. Harmon, Leslie Hodges-Gallagher, Peter J. Kushner, Geoffrey L. Greene. OP-1250 prevents tumor spread in a model of metastatic mutant ERα+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1618.
New Editorial Board Member—April 2022
Authors: Melina R. Kibbe
Journal: JAMA Surgery (2022)

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Demographic Patterns and Increasing Incidence of Cutaneous T-Cell Lymphoma in Louisiana
Authors: Jalal Maghfour, Frances Gill, Justin Olson, Nicholas Guido, Harika Echuri, Andrea Murina
Journal: JAMA Oncology (2022)

This cohort study examines the demographic characteristics associated with the incidence of cutaneous T-cell lymphoma from 2000 to 2018 in Louisiana.
Abstract 6299: Population kinetics (PopKin) of non-small cell lung cancer (NSCLC) adjuvant therapy
Authors: David J. Stewart
Journal: Cancer Research (2022)

Abstract Background: Disease-free survival (DFS) and overall survival (OS) follow 1st order kinetics. Curve Popkin assessment yields biological insights. Chemotherapy (chemo) improves outcome in resected NSCLC. We performed adjuvant DFS and OS PopKin assessments. Methods: We digitized published DFS and OS curves. We used GraphPad Prism for curve exponential decay nonlinear regression analysis (EDNLRA). Results: We assessed 1 trial with adjuvant osimertinib and 5 with platinum-based postoperative chemo and control arms. With osimertinib, DFS and OS curves were convex on log-linear plots, suggesting rapid tumor regrowth once therapy is discontinued. In chemo trials, 10 of 10 DFS curves and 9 of 10 OS curves fit 2-phase decay EDNLRA models (Table 1). Popkin calculations indicate that of control patients destined to recur, 12% would recur by 2 months after surgery, 22% by 4 months and 31% by 6 months. Conclusion: PopKin suggests osimertinib delays recurrence rather than preventing it. Combined chemo analyses suggest chemo converts 15% of patients from rapidly to slowly recurring, but many “shifted” patients eventually recur. Hence, chemo may induce reversible tumor senescence rather than eradicating micrometastases. Anti-senescent cell strategies might prove beneficial. Frequent scans are warranted in the 1st postoperative year for early detection of recurrences. Table 1. EDNLRA of adjuvant chemo and control DFS and OS curves Arm Overall t1/2 a % Fastb Fast group t1/2 c % Slowd Slow group t1/2 e Control DFS 40.1 57 11.0 43 212.7 Chemo DFS 47.2 42 11.7 58 120.8 Control OS 51.9 69 25.8 31 1.3 x 1012 Chemo OSf 61.4 75 45.9 25 1.3 x 1012 aMedian t1/2 (half-life, months) on 1-phase decay EDNLRA. bMedian % of all patients in rapidly recurring/dying subgroup on 2-phase decay EDNLRA. cMedian t1/2 in rapidly recurring/dying subgroup on 2-phase decay EDNLRA. dMedian % in slowly recurring/dying subgroup. eMedian t1/2 in slowly recurring/dying subgroup. fIn 1 study, OS curve did not fit a 2-phase decay model Citation Format: David J. Stewart. Population kinetics (PopKin) of non-small cell lung cancer (NSCLC) adjuvant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6299.